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New Drug Introduction: Epclusa®/ sofosbuvir/velpatasvir Pharmacology Manufacturer Approval Date Indications Contraindications Black Box Warnings Warnings/ Precautions Pregnancy Lactation Pharmacokinetics Drug Interactions – Object Drugs Drug Interactions – Precipitant drugs Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor that disrupts viral replication by acting as a RNA chain terminator. Velpatasvir prevents viral replication via inhibition of NS5A protein. Gilead Sciences, Inc June 28, 2016 Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection Without cirrhosis or with compensated cirrhosis (Child-Pugh A) With decompensated cirrhosis (Child-Pugh B or C) in combination with ribavirin Same as patients for whom ribavirin is contraindicated Hemoglobinopathy Renal impairment (CrCl < 50 mL/min; Ribasphere/Rebetol forumalation only) Pregnant women Coadministration with didanosine Ribavirin may cause hemolytic anemia which can result in worsening cardiac disease and lead to fatal/nonfatal myocardial infarctions. Do not treat patients with a history of significant or unstable cardiac disease. Serious symptomatic bradycardia may occur in patients taking amiodarone, especially in patients also taking beta blockers, underlying cardiac comorbidities and/or advanced liver disease Coadministration of amiodarone is not recommended. If used with amiodarone, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration followed by outpatient daily heart rate monitoring for at least the first 2 weeks of treatment Risk of reduced therapeutic effect due to concomitant inducers of PGP and/or moderate to potent inducers of CYP 2B6/3A4/2C8 Contraindicated in pregnant women and men whose female partners are pregnant if administered with ribavirin No human data available to establish risk to pregnancy outcomes. Unknown if excreted in human breast milk but was excreted in the milk of treated rats; benefits and risks should be weighed Sofosbuvir Velpatasvir A Tmax 0.5-1h 3h Effect of high fat meal 78% 21% (relative to fasting) D % Bound 61-65 >99.5 Blood to plasma ratio 0.7 0.52-0.67 M Metabolism Active Metabolite GSCYP2B6 461203; Inactive Metabolite CYP2C8 GS-331007 CYP3A4 E % Urine 80 0.4 % Fecal 14 94 T1/2 (h) SOF: 0.5; GS-331007: 25 15 Velpatasvir is an inhibitor of P-gp, BCRP, and OAT. Sofosbuvir/velpatasvir may increase the concentration of topotecan, digoxin, tenofovir, rosuvastatin, and atorvastatin Antacids, H2RA, PPI, and efavirenz may decrease the concentration of velpatasvir. Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifampin, tipranavir/ritonavir, and St. John’s wort may decrease concentration of sofosbuvir/velpatasvir. Adverse Effects Results shown for ASTRAL-1 trial Monitoring Efficacy/Toxicity Dosing – Initial/Usual/Max Renal Adjustment Hepatic Adjustment Headache (29) [28] Fatigue (20) [20] Nasopharyngitis (13) [10] Nausea (12) [11] Diarrhea (8) [7] Asthenia (7) [8] Determine hepatitis C genotype prior to initiation of therapy. A reduction in HCV RNA viral load may indicate efficacy. Monitor hemoglobin (at baseline, weeks 2 & 4, then periodically) in patients with decompensated cirrhosis who are coadministered ribavirin. Pts w/o cirrhosis and patients with compensated cirrhosis (Child-Pugh A) Sofosbuvir 400 mg / velpatasvir 100 mg once daily +/- food for 12 weeks Patients with decompensated cirrhosis Sofosbuvir 400 mg / velpatasvir 100 mg once daily with or without food + ribavirin for 12 weeks <75 kg: Ribavirin 1000 mg/day with food in 2 divided doses ≥ 75 kg: Ribavirin 1200 mg/day with food in 2 divided doses No dose adjustment for mild or moderate renal impairment The safety and efficacy in severe renal impairment (eGFR <30 mL/min/1.73m2) or ESRD requiring hemodialysis has not been established. No adjustment necessary Cost: Source: UpToDate 09/26/16 Drug Name Zepatier (elbasvir/grazoprevir) Harvoni (ledipasvir/sofosbuvir) Epclusa (sofosbuvir/velpatasvir) Dosing $ (tablets) elbasvir 50 mg/grazoprevir 100 mg daily Ledispavir 90 mg/ sofosbuvir 400 mg daily Sofosbuvir 400 mg/100 mg daily 10,920(14) 37,800 (28) 29,9904 (28) Summary Epclusa is a fixed dose combination of sofosbuvir, a hepatitis C virus nucleotide analog NS5B polymerase inhibitor and velpatasvir a HCV NS5A inhibitor indicated for the treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6. Dosing is sofosbuvir 400 mg / velpatasvir 100 mg by mouth daily for 12 weeks for patients without cirrhosis and patients with compensated cirrhosis. Ribavirin is added for 12 weeks for patients with decompensated cirrhosis. Ribavirin may cause hemolytic anemia. Monitor hemoglobin (at baseline, weeks 2 & 4, then periodically) in patients with decompensated cirrhosis coadministered ribavirin. Ribavirin is contraindicated in pregnancy and patients with hemoglobinopathies. Place in therapy: Epclusa is a first line option for HCV genotypes 1, 2, 3, 4, 5, or 6 References: 1. https://www.epclusainfo.com/ 2. Epclusa (sofosbuvir and velpatasvir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; June 2016. 3. Feld, J.J, et al. Sofosbuvir and velpatasvir for hcv genotype 1, 2, 3, 4, 5, and 6 infection. N Engl J Med 2015; 373:2599-607. 4. Foster, G.R., et al. Sofosbuvir and velpatasvir for hcv genotype 2 and 3 infection. N Engl J Med 2015; 373:2608-17. 5. Curry, M.P., et al. Sofosbuvir and velpatasvir for hcv in patients with decompensated cirrhosis. N Engl J Med 2015; 373:2618-28. Date Prepared: 09/25/2016 Editor: Peter G. Koval, Pharm.D., BCPS Author: Kelsy Combs, Pharm.D, PGY1 Ambulatory Care Pharmacy Resident